Pathogenic events including the increased generation of the neurotoxic4 kDa peptide, ABeta, are believed to be central for Alzheimer's disease (AD). Processing of the amyloid precursor protein (APP) produces ABeta, the neuroprotective APPsa and the APP intracellular domain (AID/AICD) involved in transcriptional regulation. In 1996, we identified FE65L1 as a member of a protein family that binds the APP C-terminal domain. Because the FE65 proteins influence APP processing and bind to the region of APP implicated in transcriptional regulation, understanding their biological role should provide information about this APP-dependent signaling pathway. In this competing renewal, we will address the newly identified functions of FE65 (as a component of a transcription complex) and determine whether other FE65 protein family members play a role in this cellular pathway. The aims proposed are designed to address whether the interaction of the FE65 proteins with APP is regulated. We also propose to gain an understanding of the impact of the interactions between the FE65 protein family members on APP processing and APP function with the goal of understanding whether these interactions are relevant to AD. These questions will be addressed in cell lines overexpressing the FE65 protein family members and in brain of WT mice and mice deficient for FE65 and FE65L1. The proposed experiments should supply information on the function of the FE65 proteins and the biological significance of the protein complexes containing the FE65 proteins and the amyloid precursor protein in cells of the central nervous system. In addition, we will gain insight into the role of the FE65 proteins in cellular signaling events that are critical for brain function.